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Effects of Terlipressin As Early Treatment for Protection of Brain in A Ida et al. Critical Care (2015) 19:107 DOI 10.1186/s13054-015-0825-9 RESEARCH Open Access Effects of terlipressin as early treatment for protection of brain in a model of haemorrhagic shock Keila Kazue Ida1,2*, Denise Aya Otsuki1, Adolfo Toshiro Cotarelli Sasaki1, Emilyn Silva Borges1, Letícia Urbano Cardoso Castro3, Talita Rojas Sanches3, Maria-Heloisa Massola Shimizu3, Lúcia Conceição Andrade3, José-Otávio Costa Auler Jr1, Alex Dyson4, Kenneth John Smith2, Joel Avancini Rocha Filho5 and Luiz-Marcelo Sá Malbouisson1 Abstract Introduction: We investigated whether treatment with terlipressin during recovery from hypotension due to haemorrhagic shock (HS) is effective in restoring cerebral perfusion pressure (CPP) and brain tissue markers of water balance, oxidative stress and apoptosis. Methods: In this randomised controlled study, animals undergoing HS (target mean arterial pressure (MAP) 40 mmHg for 30 minutes) were randomised to receive lactated Ringer’s solution (LR group; n =14; volume equal to three times thevolumebled),terlipressin(TERLIgroup;n =14; 2-mg bolus), no treatment (HAEMO group; n =12) or sham (n =6). CPP, systemic haemodynamics (thermodilution technique) and blood gas analyses were registered at baseline, shock and 5, 30, 60 (T60), 90 and 120 minutes after treatment (T120). After the animals were killed, brain tissue samples were obtained to measure markers of water balance (aquaporin-4 (AQP4)), Na+-K+-2Cl− co-transporter (NKCC1)), oxidative stress (thiobarbituric acid reactive substances (TBARS) and manganese superoxide dismutase (MnSOD)) and apoptotic damage (Bcl-x and Bax). Results: Despite the HS-induced decrease in cardiac output (CO) and hyperlactataemia, resuscitation with terlipressin recovered MAP and resulted in restoration of CPP and in cerebral protection expressed by normalisation of AQP4, NKCC1, TBARS and MnSOD expression and Bcl-x/Bax ratio at T60 and T120 compared with sham animals. In the LR group, CO and blood lactate levels were recovered, but the CPP and MAP were significantly decreased and TBARS levels and AQP4, NKCC1 and MnSOD expression and Bcl-x/Bax ratio were significantly increased at T60 and T120 compared with the sham group. Conclusions: During recovery from HS-induced hypotension, terlipressin was effective in normalising CPP and cerebral markers of water balance, oxidative damage and apoptosis. The role of this pressor agent on brain perfusion in HS requires further investigation. * Correspondence: [email protected] 1Laboratório de Investigação Médica (LIM-08), Disciplina de Anestesiologia, Faculdade de Medicina, Universidade de São Paulo, Avenida Doutor Arnaldo, 455, 2° andar, sala 2120, Cerqueira César, São Paulo, SP 01246-903, Brazil 2Department of Neuroinflammation, Institute of Neurology, University College London (UCL), 1 Wakefield Street, 2nd floor, WC1N 1PJ, London, UK Full list of author information is available at the end of the article © 2015 Ida et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Ida et al. Critical Care (2015) 19:107 Page 2 of 14 Introduction rates in animal studies of haemorrhagic shock [14,21]. It Haemorrhagic shock is the leading cause of early death has been reported that terlipressin can improve CPP in in trauma patients [1]. During the pre-hospital period, patients with acute liver failure [17], septic shock [22] and haemorrhage contributes to death in 33% to 56% of traumatic brain injury with catecholamine-resistant cases, and it is the most common cause of death among shock [23]. However, the effects of terlipressin on those found dead upon the arrival of emergency medical cerebral haemodynamics during early treatment for services personnel [2]. Neurological signs such as altered haemorrhagic shock remain unclear, and no data are mental state, which typically includes obtundation, available comparing the effects of resuscitation with disorientation, confusion, agitation and irritability, cannot terlipressin with those of standard fluid. be neglected, because cerebral hypoperfusion is a conse- We hypothesised that early recovery of haemorrhagic quence in patients experiencing bleeding-associated shock-induced hypotension with terlipressin could restore hypotension [3-5]. In addition, animal studies of haemor- CPP and improve oxygenation of the brain. Therefore, the rhagic shock have shown that cerebral ischaemia with purpose of the present study was to investigate the effects cell damage begins at the onset of the haemodynamic of early administration of terlipressin on CPP and brain impairment [6-8]. tissue oxygen pressure (PbtO2), as well as on the regula- Under hypotensive conditions such as those in haemor- tion of tissue markers of water balance (that is, AQP4 and rhagic shock, cerebral perfusion pressure (CPP) is NKCC1), oxidative stress (that is, TBARS and MnSOD) sustained below the lower limits of autoregulation and apoptosis (that is, Bax and Bcl-x) within the brain in a [8], which is detrimental to brain tissue oxygenation porcine model of haemorrhagic shock. [5,7,9]. Cerebral ischaemia has been associated with dysregulation of aquaporin-4 (AQP4) and Na+-K+-2Cl − Materials and methods co-transporter (NKCC1) in the astrocytes [9,10] and Bcl-2 Ethical approval related apoptotic proteins in the neurons [11]. Oxidative This prospective randomised experimental study was stress is implicated in the neuronal apoptosis that occurs approved by the Comissão de Ética em Pesquisa of in haemorrhagic shock. It has been shown to accompany the Hospital das Clínicas at Faculdade de Medicina of increased lipid peroxidation within the brain, as reflected Universidade de São Paulo (067/11 and 280/13). by changes in the levels of thiobarbituric acid reactive substances (TBARS) and changes in the expression of Surgical preparation and monitoring antioxidant enzymes such as manganese superoxide Female Large White pigs (n =46) weighing 20 to 30 kg dismutase (MnSOD) [12]. were fasted for 12 hours with free access to water Standard resuscitation practice for haemorrhagic shock before the experiments. The animals were premedicated mandates use of high-volume crystalloids. However, such with ketamine (5 mg/kg intramuscular) and midazolam therapy can result in adverse effects such as interstitial (0.25 mg/kg intramuscular), and anaesthesia was induced oedema in the gut and cellular oedema in the heart [13], with propofol (7 mg/kg intravenous). After endotracheal increases in the inflammatory cytokine profile [14] and intubation, anaesthesia was maintained with isoflurane increased intracranial pressure (ICP) [8]. Crystalloids may vaporized in 40% oxygen, and the pigs were ventilated also fail to recover CPP and oxygenation within the brain (Fabius GS Premium; Dräger, Lübeck, Germany) with a [8,15]. Terlipressin is a synthetic, long-acting (4 to 6 hours) tidal volume of 8 ml/kg and positive end-expiratory pres- analogue of vasopressin. The structure of terlipressin con- sure of 5 cmH2O. The respiratory rate was adjusted to tains a peptide that represents the natural hormone lysine maintain normocapnia (partial pressure of carbon dioxide vasopressin, the innate vasopressin analogue in pigs. Its in arterial blood (PaCO2) between 35 and 45 mmHg). structure is very similar to human arginine vasopressin, Lactated Ringer’s solution (4 ml/kg/hr) and pancuronium but the synthetic drug is characterised by a more specific (0.3 mg/kg/hr) were administered continuously through- V1 agonistic effect (V1:V2 ratio =2.2:1) compared with out the experiments. Body temperature was maintained arginine-vasopressin (V1:V2 ratio =1:1). Terlipressin has at 38°C using a heated mat (Medi-Therm II; Gaymar been studied as a vasoactive drug in the management of Industries, Orchard Park, NY, USA). catecholamine-resistant arterial hypotension in septic Both femoral arteries were catheterised for measurement shock [16], liver failure [17] and acute gastrointestinal of mean arterial pressure (MAP) and withdrawal of blood bleeding [18]. The effects of terlipressin consist of to induce haemorrhagic shock, respectively. Another vasoconstrictive activity on vascular smooth muscle catheter was inserted into the right femoral vein for cells and a pronounced vasoconstriction within the later administration of treatments. splanchnic circulation that has been shown to redistribute A 7.5-French pulmonary artery catheter (Swan-Ganz; blood flow to recover perfusion pressure to organs such as Edwards Lifesciences, Irvine, CA, USA) was surgically the liver, kidney and brain [19,20] and to increase survival introduced into the right internal jugular vein and advanced Ida et al. Critical Care (2015) 19:107 Page 3 of 14 under continuous pressure recording into wedge position. Randomisation was previously performed, and the blind Cardiac output was determined by bolus pulmonary artery allocation of the pigs among groups was placed in thermodilution (Vigilance monitor; Edwards Lifesciences). numbered manila envelopes, which were opened in a All catheters and pressure transducers were filled with consecutive manner immediately before baseline mea- isotonic saline containing heparin
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